Macrophage migration inhibitory factor (MIF) is expressed and secreted in response to mitogens and integrin-dependent cell adhesion. Once released, autocrine MIF promotes the activation of RhoA ...GTPase leading to cell cycle progression in rodent fibroblasts. We now report that small interfering RNA-mediated knockdown of MIF and MIF small molecule antagonism results in a greater than 90% loss of both the migratory and invasive potential of human lung adenocarcinoma cells. Correlating with these phenotypes is a substantial reduction in steady state as well as serum-induced effector binding activity of the Rho GTPase family member, Rac1, in MIF-deficient cells. Conversely, MIF overexpression by adenovirus in human lung adenocarcinoma cells induces a dramatic enhancement of cell migration, and co-expression of a dominant interfering mutant of Rac1 (Rac1N17) completely abrogates this effect. Finally, our results indicate that MIF depletion results in defective partitioning of Rac1 to caveolin-containing membrane microdomains, raising the possibility that MIF promotes Rac1 activity and subsequent tumor cell motility through lipid raft stabilization.
Vaccinia virus (VACV) encodes an anti-apoptotic Bcl-2-like protein F1 that acts as an inhibitor of caspase-9 and of the Bak/Bax checkpoint but the role of this gene in immune responses is not known. ...Because dendritic cells that have phagocytosed apoptotic infected cells cross-present viral antigens to cytotoxic T cells inducing an antigen-specific immunity, we hypothesized that deletion of the viral anti-apoptotic F1L gene might have a profound effect on the capacity of poxvirus vectors to activate specific immune responses to virus-expressed recombinant antigens. This has been tested in a mouse model with an F1L deletion mutant of the HIV/AIDS vaccine candidate MVA-C that expresses Env and Gag-Pol-Nef antigens (MVA-C-ΔF1L). The viral gene F1L is not required for virus replication in cultured cells and its deletion in MVA-C induces extensive apoptosis and expression of immunomodulatory genes in infected cells. Analysis of the immune responses induced in BALB/c mice after DNA prime/MVA boost revealed that, in comparison with parental MVA-C, the mutant MVA-C-ΔF1L improves the magnitude of the HIV-1-specific CD8 T cell adaptive immune responses and impacts on the CD8 T cell memory phase by enhancing the magnitude of the response, reducing the contraction phase and changing the memory differentiation pattern. These findings reveal the immunomodulatory role of F1L and that the loss of this gene is a valid strategy for the optimization of MVA as vaccine vector.
Sirtuin 5 (SIRT5) is a member of the family of NAD
-dependent lysine/histone deacetylases. SIRT5 resides mainly in the mitochondria where it catalyzes deacetylation, demalonylation, desuccinylation, ...and deglutarylation of lysine to regulate metabolic and oxidative stress response pathways. Pharmacologic inhibitors of SIRT5 are under development for oncologic conditions, but nothing is known about the impact of SIRT5 on antimicrobial innate immune defenses. Using SIRT5 knockout mice, we show that SIRT5 deficiency does not affect immune cell development, cytokine production and proliferation by macrophages and splenocytes exposed to microbial and immunological stimuli. Moreover, preclinical models suggest that SIRT5 deficiency does not worsen endotoxemia,
and
pneumonia,
peritonitis, listeriosis, and staphylococcal infection. Altogether, these data support the safety profile in terms of susceptibility to infections of SIRT5 inhibitors under development.
In France, the reform of the individualized transport sector comes along with the emergence of new digital platforms, around which new mobility services are being developed. The expansion of these ...new players and the specific characteristics of their economic model are causing many transformations. They test the traditional foundations of the economy of the involved activities, the structure of the industry and that of the market. The dysfunctions that are inherent to these developments have repercussions on the socio-economic conditions of the drivers and their work layout. This article discusses the effects of service digitization in the individualized transport sector in France. It shows how the aggregation of technological resources and the changes in the political and economic environment contribute to the emergence of a new order in which business practices are being deployed, affecting the structure of trades, employment relations and working conditions.
The presence of processed birds in the archeological faunal record is considered key to assessing human dietary evolution. Taphonomic studies on birds from sites older than Marine Isotope Stage (MIS) ...2 have become relevant in the last few years, leading to the proposal of more complex scenarios of human subsistence. Several works have demonstrated direct evidence of bird consumption by
Homo
prior to anatomically modern humans in Europe; however, others support the hypothesis of non-anthropogenic bird accumulations. This has led to the necessity of determining what elements or factors cause the human exploitation of birds in some archeological sites before the end of the Pleistocene. The Grotte des Barasses II site is located within this framework. Short-term human occupations have been attested by the presence of lithic tools and processed macrofaunal remains. Additionally, a small assemblage of bird bones has also been recovered. Here, we present a detailed taphonomic study with the aim of exploring possible relationships between these avian taxa and human occupations. Despite the fact that Neanderthals inhabited the cave, avian specimens show damage pointing to different causative agents. Direct evidence (digestion, gnawing) indicates that mammalian carnivores and nocturnal raptors were mainly involved in the accumulation of bird bones. We propose some factors that might determine whether or not small game was exploited in this specific locality and emphasize the importance of such analytical approaches in the general interpretations of the Pleistocene sites.
Type B trichotecens such as deoxynivalenol (DON), 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), nivalenol (NIV) and zearalenone (ZEN) are mycotoxins contaminating wheat and ...wheat dust. Mycotoxins are toxic upon ingestion and considered potentially toxic when inhaled. Whereas dietary exposure to mycotoxins is controlled in food, data on occupational exposure by inhalation by grain workers are scarce. The objectives of this study were to determine the incidence of DON, 3-ADON, 15-ADON, NIV and ZEN in aerosols generated during grain harvesting and unloading and the risk of exposure of grain workers. Aerosols were collected during the threshing of 78 winter wheat fields and grain unloading of 59 grain lots in six grain terminals in the Vaud region (Switzerland). The samples represented the diversity of the winter wheat cultivar and of the farming system (88 treated with fungicides, 46 untreated). Using a HPLC MS/MS method developed to quantify mycotoxins in aerosols, we report that the mycotoxin content of aerosols was not affected by the wheat cultivars or farming system, but that the incidence of the mycotoxins differed between activities. While wheat harvesting generated on average 28, 20 and 1 ng·m
of DON, NIV and ZEN, respectively, grain unloading generated 53, 46 and 4 ng·m
. Personal sampling revealed that working in a cab was an efficient protective measure. However, it was not sufficient to avoid chronic exposure to multiple mycotoxins. The most exposed activity was the cleaning, exposing workers to DON, NIV and ZEN at concentrations as high as 65, 59 and 3 ng·m
. These data provide valuable information for future studies of mycotoxin toxicity at relevant concentrations on respiratory health.
Suppurative thrombophlebitis of the portal-mesenteric venous system occurring in the setting of abdominal inflammatory and infectious processes is a serious condition that can lead to septic shock, ...bowel ischemia, hepatic abscess, and death if unrecognized. Diagnosis is often delayed because symptoms are aspecific and pain at the primary site of infection may be mild. Contrast-enhanced CT scans can diagnose both portal thrombosis and a primary infection site. Treatment may include early resective surgery in case of appendicitis or diverticulitis, in association with large-spectrum antibiotics and possibly anticoagulation. A characteristic of suppurative thrombophlebitis, whether splanchnic or systemic, is the latency before the effects of antibiotic therapy are seen. Anticoagulation can be administered to avoid extension to the superior mesenteric vein. We presented a critically ill 53-year-old man with chronic colonic diverticulitis complicated by suppurative emphysematous portal-mesenteric thrombophlebitis with only a slow response to large-spectrum antibiotics.
Glioblastoma is considered the most common malignant primary tumor of central nervous system. In spite of the current standard and multimodal treatment, the prognosis of glioblastoma is poor. For ...this reason, new therapeutic approaches need to be developed to improve the survival time of the glioblastoma patient. In this study, we performed a preclinical experiment to evaluate therapeutic efficacy of
166
Ho microparticle suspension administered by microbrachytherapy on a minipig glioblastoma model. Twelve minipigs were divided in 3 groups. Minipigs had injections into the tumor, containing microparticle suspensions of either
166
Ho (group 1; n = 6) or
165
Ho (group 2; n = 3) and control group (group 3;
n
= 3). The survival time from treatment to euthanasia was 66 days with a good state of health of all minipigs in group 1. The median survival time from treatment to tumor related death were 8.6 and 7.3 days in groups 2 and control, respectively. Statistically, the prolonged life of group 1 was significantly different from the two other groups (p < 0.01), and no significant difference was observed between group 2 and control (p=0.09). Our trial on the therapeutic effect of the
166
Ho microparticle demonstrated an excellent efficacy in tumor control. The histological and immunohistochemical analysis showed that the efficacy was related to a severe
166
Ho induced necrosis combined with an immune response due to the presence of the radioactive microparticles inside the tumors. The absence of reflux following the injections confirms the safety of the injection device.
Glioblastomas (GBMs) are the most frequent and malignant brain tumors in adults. Glucocorticoids (GCs) are routinely used in the treatment of GBMs for their capacity to reduce the tumor-associated ...edema. Few in vitro studies have suggested that GCs inhibit the migration and invasion of GBM cells through the induction of MAPK phosphatase 1 (MKP-1). Macrophage migration inhibitory factor (MIF), an endogenous GC antagonist is up-regulated in GBMs. Recently, MIF has been involved in tumor growth and migration/invasion and specific MIF inhibitors have been developed on their capacity to block its enzymatic tautomerase activity site. In this study, we characterized several glioma cell lines for their MIF production. U373 MG cells were selected for their very low endogenous levels of MIF. We showed that dexamethasone inhibits the migration and invasion of U373 MG cells, through a glucocorticoid receptor (GR)- dependent inhibition of the ERK1/2 MAPK pathway. Oppositely, we found that exogenous MIF increases U373 MG migration and invasion through the stimulation of the ERK1/2 MAP kinase pathway and that this activation is CD74 independent. Finally, we used the Hs 683 glioma cells that are resistant to GCs and produce high levels of endogenous MIF, and showed that the specific MIF inhibitor ISO-1 could restore dexamethasone sensitivity in these cells. Collectively, our results indicate an intricate pathway between MIF expression and GC resistance. They suggest that MIF inhibitors could increase the response of GBMs to corticotherapy.
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